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Am J Perinatol 2022; 39(07): 717-725
DOI: 10.1055/s-0040-1718880
Review Article

Ampicillin Dose for Early and Late-Onset Group B Streptococcal Disease in Neonates

Sin Yin Lim
1   Division of Pharmacy Practice, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin
,
Jamie L. Miller
2   Division of Pharmacy Practice, Department of Pharmacy, Clinical and Administrative Sciences, University of Oklahoma Health Sciences Center College of Pharmacy, Oklahoma City, Oklahoma
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Abstract

Ampicillin is frequently used in neonates for early- and late-onset group B streptococcal (GBS) disease. In 2019, the American Academy of Pediatrics (AAP) published guidelines for GBS which included updated dosing recommendations for ampicillin for bacteremia and provided specific dosing recommendations for meningitis. The dosing recommendations in the guidelines were based off the 2018 Report of the Committee on Infectious Diseases (i.e., Red Book), which differed from the 2015 Red Book. For bacteremia, no dosing changes were recommended for ampicillin dosing in neonates ≤ 7 days of postnatal age (PNA), but less frequent dosing intervals were recommended for neonates > 7 days PNA. For meningitis, increased dosing recommendations were provided in the update. However, the rationale and supporting evidence for these changes were not provided. A literature search was performed to review articles pertaining to the pharmacokinetics (PK), pharmacodynamics (PD) and safety of ampicillin in neonates. The ampicillin dosing recommendations in the AAP guidelines were mainly supported by a 2014 publication that evaluated the PK and PD of ampicillin in neonates with gestational age (GA) of 24 to 41 weeks and PNA of 0 to 25 days. The proposed dosing from this study for bacteremia is included in the 2018 Red Book and 2019 guidelines. For meningitis, no supporting evidence was identified for the dosing recommendations in the 2018 Red Book and 2019 guidelines. Only one study has evaluated ampicillin concentrations in cerebrospinal fluid, but proposed dosing from this study was much lower than that included in the guidelines. The high ampicillin doses for GBS meningitis should be used with caution, as high ampicillin concentrations have been associated with seizures and no studies have evaluated efficacy of this dosing strategy. The purpose of this review is to identify key pieces of literature regarding dosing recommendations and safety of ampicillin in neonates.

Key Points

  • Recent guidelines provide dosing recommendations for ampicillin, but the supporting evidence is not included.

  • Literature supporting evidence for ampicillin dosing for bacteremia is available, but not for dosing for meningitis.

  • Recommended meningitis dose may result in supratherapeutic concentrations and increase seizure risk.

Keywords

ampicillin - neonate - pharmacokinetics - pharmacodynamics - safety


Publication History

Received: 23 July 2020

Accepted: 15 September 2020

Article published online:
22 October 2020

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  • References

  • 1 Puopolo KM, Benitz WE, Zaoutis TE. Committee on Fetus and Newborn, Committee on Infectious Diseases. Management of neonates born at ≤ 34 6/7 weeks' gestation with suspected or proven early-onset bacterial sepsis. Pediatrics 2018; 142 (06) e20182896
    CrossrefPubMedGoogle Scholar
  • 2 Puopolo KM, Benitz WE, Zaoutis TE. The American Academy of Pediatrics Committee on Fetus and Newborn and American Academy of Pediatrics Committee on Infectious Diseases. Management of neonates born at > 35 0/7 weeks’ gestation with suspected or proven early-onset bacterial sepsis. Pediatrics 2018; 142 (06) e20182894
    CrossrefPubMedGoogle Scholar
  • 3 Schrag SJ, Farley MM, Petit S. et al. Epidemiology of invasive early-onset neonatal sepsis, 2005 to 2014. Pediatrics 2016; 138 (06) e20162013
    CrossrefPubMedGoogle Scholar
  • 4 Nanduri SA, Petit S, Smelser C. et al. Epidemiology of invasive early-onset and late-onset group B streptococcal disease in the United States, 2006 to 2015: multistate laboratory and population-based surveillance. JAMA Pediatr 2019; 173 (03) 224-233
    CrossrefPubMedGoogle Scholar
  • 5 Puopolo KM, Lynfield R, Cummings JJ. Committee on Fetus and Newborn, Committee on Infectious Diseases. Management of infants at risk for group B streptococcal disease. Pediatrics 2019; 144 (02) e20191881
    CrossrefPubMedGoogle Scholar
  • 6 American Academy of Pediatrics. Antibacterial drugs for neonates (<28 postnatal days of age). In: Kimberlin DW, Brady MT, Jackson MA, Long SS. , eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed.. Itasca, IL: American Academy of Pediatrics; 2018: 915-919
    Google Scholar
  • 7 American Academy of Pediatrics. 2018 Nelson's Pediatric Antimicrobial Therapy. 24th ed.. Itasca, IL: American Academy of Pediatrics; 2018
    Google Scholar
  • 8 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6 (07) e1000097
    Google Scholar
  • 9 Cies JJ, Fugarolas KN, Moore II WS, Mason RW, Menkiti OR. Population pharmacokinetics and pharmacodynamic target attainment of ampicillin in neonates with hypoxemic-ischemic encephalopathy in the setting of controlled hypothermia. Pharmacotherapy 2017; 37 (04) 456-463
    CrossrefPubMedGoogle Scholar
  • 10 Tremoulet A, Le J, Poindexter B. et al; Administrative Core Committee of the Best Pharmaceuticals for Children Act-Pediatric Trials Network. Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design. Antimicrob Agents Chemother 2014; 58 (06) 3013-3020
    CrossrefPubMedGoogle Scholar
  • 11 Sutton AM, Turner TL, Cockburn F, McAllister TA. Pharmacokinetic study of sulbactam and ampicillin administered concomitantly by intraarterial or intravenous infusion in the newborn. Rev Infect Dis 1986; 8 (Suppl. 05) S518-S522
    CrossrefPubMedGoogle Scholar
  • 12 Dahl LB, Melby K, Gutteberg TJ, Størvold G. Serum levels of ampicillin and gentamycin in neonates of varying gestational age. Eur J Pediatr 1986; 145 (03) 218-221
    CrossrefPubMedGoogle Scholar
  • 13 Driessen OMJ, Sorgedrager N, Michel MF, Kerrebijn KF, Hermans J. Variability and predictability of the plasma concentration of ampicillin and kanamycin in new-born infants. Eur J Clin Pharmacol 1979; 15 (02) 133-137
    CrossrefPubMedGoogle Scholar
  • 14 Driessen OMJ, Sorgedrager N, Michel MF. Pharmacokinetic aspects of therapy with ampicillin and kanamycin in new-born infants. Eur J Clin Pharmacol 1978; 13 (06) 449-457
    CrossrefPubMedGoogle Scholar
  • 15 Hermans J, Driessen O, Sorgedrager N, Spoor M. Pharmacokinetic analysis of ampicillin concentration in neonates: comparison of two pharmacokinetic models and of two numerical methods. Arzneimittelforschung 1975; 25 (06) 947-949
    PubMedGoogle Scholar
  • 16 Kaplan JM, McCracken Jr. GH, Horton LJ, Thomas ML, Davis N. Pharmacologic studies in neonates given large dosages of ampicillin. J Pediatr 1974; 84 (04) 571-577
    CrossrefPubMedGoogle Scholar
  • 17 Axline SG, Yaffe SJ, Simon HJ. Clinical pharmacology of antimicrobials in premature infants. II. Ampicillin, methicillin, oxacillin, neomycin, and colistin. Pediatrics 1967; 39 (01) 97-107
    CrossrefPubMedGoogle Scholar
  • 18 Boe RW, Williams CP, Bennett JV, Oliver Jr TK. Serum levels of methicillin and ampicillin in newborn and premature infants in relation to postnatal age. Pediatrics 1967; 39 (02) 194-201
    CrossrefPubMedGoogle Scholar
  • 19 Ericson JE, Hornik CP, Greenberg RG. et al; Best Pharmaceuticals for Children Act – Pediatric Trials Network. Paradoxical antibiotic effect of ampicillin: use of a population pharmacokinetic model to evaluate a clinical correlate of the eagle effect in infants with bacteremia. Pediatr Infect Dis J 2020; 39 (08) 725-729
    CrossrefPubMedGoogle Scholar
  • 20 Sheffield MJ, Lambert DK, Henry E, Christensen RD. Effect of ampicillin on the bleeding time of neonatal intensive care unit patients. J Perinatol 2010; 30 (08) 527-530
    CrossrefPubMedGoogle Scholar
  • 21 Sheffield MJ, Lambert DK, Baer VL. et al. Effect of ampicillin on bleeding time in very low birth-weight neonates during the first week after birth. J Perinatol 2011; 31 (07) 477-480
    CrossrefPubMedGoogle Scholar
  • 22 Hornik CP, Benjamin Jr. DK, Smith PB. et al; Best Pharmaceuticals for Children Act—Pediatric Trials Network. Electronic health records and pharmacokinetic modeling to assess the relationship between ampicillin exposure and seizure risk in neonates. J Pediatr 2016; 178: 125-129.e1
    CrossrefPubMedGoogle Scholar
  • 23 Yoshioka H, Takimoto M, Riley Jr HD. Pharmacokinetics of ampicillin in the newborn infant. J Infect Dis 1974; 129 (04) 461-464
    CrossrefPubMedGoogle Scholar
  • 24 Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis 1998; 27 (01) 10-22
    CrossrefPubMedGoogle Scholar
  • 25 Hodgman T, Dasta JF, Armstrong DK, Visconti JA, Reilley TE. Ampicillin-associated seizures. South Med J 1984; 77 (10) 1323-1325
    CrossrefPubMedGoogle Scholar
  • 26 Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Empiric use of ampicillin and cefotaxime, compared with ampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonatal death. Pediatrics 2006; 117 (01) 67-74
    CrossrefPubMedGoogle Scholar
  • 27 Burroughs SF, Johnson GJ. Beta-lactam antibiotics inhibit agonist-stimulated platelet calcium influx. Thromb Haemost 1993; 69 (05) 503-508
    Article in Thieme ConnectPubMedGoogle Scholar